The proposed Conte Center will seek to explore the central hypothesis that neurolcptic drugs act by affecting monoamine and glutamate signal transduction pathways. Validation of this hypothesis should provide very valuable insights into the etiology of schizophrenia and be highly relevant to the development of improved therapies for schizophrenia and related disorders. The proposed Conte Center will be comprised of 5 projects at 4 different universities. The five Pis involved have an established history of effective collaboration and will use their complementary expertise and resources to take a multi-disciplinary approach in the proposed research. The Center Director will be Paul Greengard (Project 1, Rockefeller Univ.); project leaders are Nathaniel Heintz (Project 2, Rockefeller Univ.), Angus Nairn (Project 3 leader, Yale Univ.); Eric Nestler (Project 4 leader, UT Southwestern); James Surmeier (Project 5 leader, Northwestern Univ.). In Project 3, Dr. Nairn will address the major hypothesis of the Conte Center by taking primarily biochemical and molecular approaches to characterize key signaling proteins believed to be involved in the actions of monoamines and glutamale. These studies will in part focus on studies of proteins and enzymes already implicated, from long lasting collaborative studies by Drs. Nairn and Greengard, in the actions of dopamine, serotonin and glutamate in the neostriatum. Specific Aims include: I. Characterization of the mechanism of altered dendritic structure caused by neuroleptic drugs these studies will analyze the role of the post-synaptic scaffold protein, spinophilin, in the action of neuroleptic drugs as well as characterize the role of other proteins in the long-term effects of these drugs; II. Characterization of the role of RCS (Regulator of Calniodulin Signaling) in the actions of neuroleptic drugs - these studies will analyze the role in neuroleptic action of the modulalory protein, RCS, known to be involved in mediating the actions of D2 dopamine receptors; III. Characterization of the role in neuroleptic action of novel signaling proteins interacting with GPCRsthese studies will analyze the structural basis for the interaction of a variety of GPCRs with novel interacting proteins. For each of the aims, the proposed studies will be closely linked with complementary cellular, electrophysiological and behavioral studies being performed in other Projects and Cores of the Conte Center.